On the  OH and  OOH Scavenging Activity of 3-Methyl-1-pyridin-2-yl-5-pyrazolone: Comparisons with Its Parent Compound, Edaravone Adriana Perez-Gonzalez and Annia Galano* The free radical scavenging activity of 3-methyl-1-pyridin-2-yl-5- pyrazolone (pyridyl) has been studied in aqueous and lipid solutions, using the density functional theory. Four mechanisms of reaction have been considered: single electron transfer, sequential proton electron transfer (SPET), hydrogen transfer, and radical adduct formation. It was found that the reaction with  OH occur at diffusion-limited rate, which is very similar to that of edaravone, regardless of the polarity of the environment. This indicates that they are both excellent  OH scavengers. Regarding the  OOH scavenging activity of pyridyl, in lipid media it was predicted to be about 15 times higher than that of edaravone. However, in this case they were found to be rather poor  OOH scavengers in lipid media. On the contrary, they are predicted to be excellent  OOH scavengers in aqueous solution. In fact, they were found to be among the best peroxyl radical scavengers in such medium. The rates constants of the  OOH reactions with pyridyl and edaravone, in aqueous solution, were estimated to be 1.1  10 7 and 4.3  10 8 M 1 s 1 , respectively. The outstanding scavenging activity of these compounds was attributed to the presence of their anionic forms, which are much more reactive than the neutral species. The reactions with  OOH were found to take place almost exclusively by the SPET mechanism. VC 2012 Wiley Periodicals, Inc. DOI: 10.1002/qua.24046 Introduction Living organisms are in a delicate chemical balance that is required for maintaining a healthy state and involves a huge variety of chemical compounds including reactive oxygen spe- cies (ROS). The imbalance between the ROS generation and the antioxidant defense system leads to unhealthy high con- centrations of these species and to chemical modifications of important biological molecules, such as DNA, proteins, lipids, and carbohydrates. [1,2] This imbalance is known as oxidative stress (OS) and has been associated to the initiation and devel- opment of several diseases with significant morbidity and mor- tality. Some of them are cancer, [3] cardiovascular disorders, [4] atherosclerosis, [5] and several neurological disorders including Parkinson’s and Alzheimer’s diseases. [6] Therefore, it is not surprising that searching for efficient ways of preventing, or reducing, OS and the consequent molecular damage [7] is a very active area of research. In particular new protectors against ROS, frequently referred to as antioxidants, with low toxicity are of great interest. Edaravone, also known as MCI-186, (3-methyl-1-phenyl-2-pyra- zolin-5-one, EDA, Scheme 1) is among them. It is a synthetic neuroprotective drug developed in Japan, where it has been clinically used since 2001. It was the first free radical scavenger approved for treating acute stroke caused by cerebral throm- bosis and embolism. [8] Since edaravone’s appearance, numer- ous studies have been devoted to investigate its protective effects against OS-related diseases. [9–14] Other derivatives have also been reported to present free radical scavenging activity and other beneficial properties including antiviral activity, inhibition of the agent of tuberculosis, antitumor effects, and benefits for medical treatment of cancer and related diseases. [15–20] Some of them have also been proposed to be even better scavengers than the parent molecule. A variety of edaravone derivatives have been synthesized for Nakagawa et al. [21] with substituents of different nature (electron-withdrawing groups, electron-donating groups, and p-conjugated groups) at sites 1, 3, and 4 of the pyrazolone ring (Scheme 1). They found one derivative, 3-methyl-1-pyri- din-2-yl-5-pyrazolone (pyridyl), with better antioxidant activity than edaravone when reacting with  OH by single electron transfer (SET) in aqueous solution. Hata et al. [22] determined the rate constants of the reactions of pyridyl and edaravone with oxidative radicals such as  OH and  N 3 . The reported values for the reaction of pyridyl with  OH and  N 3 were 7.8  0.1  10 9 M 1 s 1 and 4.1  0.1  10 9 M 1 s 1 , respectively. For the reaction of edaravone with  OH and  N 3 the reported rate constants are 8.5  0.4  10 9 M 1 s 1 and 5.8  0.3  10 9 M 1 s 1 , respectively. Thus, they suggested that the anti- oxidant activity of edaravone is slightly higher than that of pyridyl, contrary to what was proposed by Nakagawa et al. [21] However, it should be noted that all the aforementioned rate constants correspond to diffusion-controlled reactions. This means that both compounds are excellent for scavenging  OH but it also means that, because of its very high reactivity, this radical is not the best for comparing the antioxidant activ- ity of different species. In fact, it has been proposed that it fre- quently react within the diffusion-limit regime with a wide A. P erez-Gonz  alez, A. Galano Departamento de Quı´mica, Divisi  on de Ciencias B asicas e Ingenierı´a. Universidad Aut  onoma Metropolitana-Iztapalapa, Av San Rafael Atlixco No. 186, Col.Vicentina C.P.09340, M exico D.F. E-mail: agalano@prodigy.net.mx or agal@xanum.uam.mx VC 2012 Wiley Periodicals, Inc. International Journal of Quantum Chemistry 2012, DOI: 10.1002/qua.24046 1 WWW.Q-CHEM.ORG FULL PAPER